Acute lymphoblastic leukemia (ALL) is the most frequent childhood cancer, with T-cell ALL representing around 15% of the cases. T-cell ALL is a lymphoproliferative disorder characterized by the deregulated expansion of transformed T-cells. Despite successes in the treatment, leukemia relapse, refractory disease, induction failure, and infant leukemia represent significant challenges in pediatric ALL and pediatric T-ALL, as well as adult disease, and these diseases remain highly untreatable. In T-cell ALL (T-ALL) in particular, disease relapse and deficient response to conventional therapies are associated with poor prognosis. Therefore, the development of novel, more effective therapies for relapsed ALL is necessary.
Prior attempts have been made to develop approaches that can successfully disrupt or abrogate critical molecular effectors in leukemia relapse, refractory T-cell leukemia, and progress in the molecular characterization of T-ALL raised expectations of the development of more selective and efficient targeted therapies. Nonetheless, despite such progress, interventions targeting key oncogenic drivers, such as Notch signaling, or single molecular effectors showed limited efficacy. The challenge remains to identify master molecular regulators that control the activity of multiple complementary, non-recurrent signaling pathways in leukemia cells, integrating oncogenic signals and microenvironment cues.
An alternative to using multiple drugs to disrupt distinct molecular pathways is to target a central molecule whose function regulates multiple signaling cascades, such as the activity of distinct transcription factors (TFs) engaged by upstream signals (oncogenic events, cytokines). The compounds, compositions, and methods described herein target multiple signaling pathways that mediate or regulate key functions in drug resistance and maintenance of tumor cells, particularly in advanced disease and cancer recurrence.
It has been discovered herein that selective inhibition of the redox function of Ref-1 is useful in treating leukemia, including ALL in its various forms. The role of Ref-1 in leukemia drug-resistance and ALL relapse has heretofore been unknown. It has been discovered herein that leukemia cells, including human leukemia T-ALL cells, express Ref-1.
Without being bound by theory, it is believed herein that ALL is treatable by selectively inhibiting the redox function of Ref-1. Described herein are compounds and methods for inhibiting the redox function of Ref-1. Without being bound by theory, it is also believed herein that ALL is treatable by interfering with STAT3 signaling. Described herein are methods for directly interfering with STAT3 signaling, and indirectly interfering with STAT3 signaling.
In one illustrative embodiment of the invention, there is provided a method for treating leukemia in a patient in need thereof comprising the step of administering an effective amount of at least one Ref-1 redox inhibitor of the formula
or a pharmaceutically acceptable salt thereof, wherein R, RA, X and Y are defined below.
In addition, various genera and subgenera of each of R, RA, X and Y are described herein. It is to be understood that all possible combinations of the various genera and subgenera of each of R, RA, X and Y described herein represent additional illustrative embodiments of compounds of the invention described herein. It is to be further understood that each of those additional illustrative embodiments of compounds may be used in any of the compositions, methods, and/or uses described herein.
In another embodiment, pharmaceutical compositions containing one or more of the compounds are also described herein. In one aspect, the compositions include a therapeutically effective amount of the one or more compounds for treating a patient with a leukemia as disclosed herein. It is to be understood that the compositions may include other component and/or ingredients, including, but not limited to, other therapeutically active compounds, and/or one or more carriers, diluents, excipients, and the like. In another embodiment, methods for using the compounds and pharmaceutical compositions for treating patients with a leukemia as disclosed herein are also described herein. In one aspect, the methods include the step of administering one or more of the compounds and/or compositions described herein to a patient with a leukemia as disclosed herein. In another aspect, the methods include administering a therapeutically effective amount of the one or more compounds and/or compositions described herein for treating patients with a leukemia as disclosed herein. In another embodiment, uses of the compounds and compositions in the manufacture of a medicament for treating patients with a leukemia as disclosed herein are also described herein. In one aspect, the medicaments include a therapeutically effective amount of the one or more compounds and/or compositions for treating a patient with a leukemia as disclosed herein.
It is appreciated herein that the compounds described herein may be used alone or in combination with other compounds useful for treating a leukemia as disclosed herein, including those compounds that may be therapeutically effective by the same or different modes of action. In addition, it is appreciated herein that the compounds described herein may be used in combination with other compounds that are administered to treat other symptoms of a leukemia as disclosed herein.